PubMed Health⌕ Search

Biomedical subjects

L Bass

Publications and source records attributed to L Bass.

At least 19 recordsLinked to original sources
PubMed2001

Positron emission tomography of hepatic first-pass metabolism of ammonia in pig.

Hepatic first-pass metabolism plays a key role in metabolic regulation and drug metabolism. Metabolic processes can be quantified in vivo by positron emission tomography scanning (PET). We wished to develop a PET technique to measure hepatic first-pass metabolism of ammonia. Seven anaesthetised pigs were given positron-labelled ammonia, (13)NH(3), into the portal vein and into the vena cava as successive 2-min infusions followed by 22-min dynamic liver scanning. Vena cava infusion data were used to account for recirculation of tracer and metabolites following the portal vein infusion. The scan data were analysed by a model of sinusoidal zonation of ammonia metabolism with periportal urea formation and perivenous formation of glutamine. The hepatic extraction fraction of (13)NH(3) was 0.73+/-0.16 (mean+/-SD, n=7 pigs). Values of clearance of ammonia to urea and to glutamine were obtained, as were rate constants for washout of these two metabolites. Overall, the modelling showed half of the ammonia uptake to be converted to urea and half to glutamine. The washout rate constant for glutamine was about one-tenth of that for urea. We conclude that hepatic first-pass metabolism of ammonia was successfully assessed by PET.

Ammonia↗
PubMed2001

Liver kinetics of glucose analogs measured in pigs by PET: importance of dual-input blood sampling.

UNLABELLED: Metabolic processes studied by PET are quantified traditionally using compartmental models, which relate the time course of the tracer concentration in tissue to that in arterial blood. For liver studies, the use of arterial input may, however, cause systematic errors to the estimated kinetic parameters, because of ignorance of the dual blood supply from the hepatic artery and the portal vein to the liver. METHODS: Six pigs underwent PET after [15O]carbon monoxide inhalation, 3-O-[11C]methylglucose (MG) injection, and [18F]FDG injection. For the glucose scans, PET data were acquired for 90 min. Hepatic arterial and portal venous blood samples and flows were measured during the scan. The dual-input function was calculated as the flow-weighted input. RESULTS: For both MG and FDG, the compartmental analysis using arterial input led to systematic underestimation of the rate constants for rapid blood-tissue exchange. Furthermore, the arterial input led to absurdly low estimates for the extracellular volume compared with the independently measured hepatic blood volume of 0.25 +/- 0.01 mL/mL (milliliter blood per milliliter liver tissue). In contrast, the use of a dual-input function provided parameter estimates that were in agreement with liver physiology. Using the dual-input function, the clearances into the liver cells (K1 = 1.11 +/- 0.11 mL/min/mL for MG; K1 = 1.07 +/- 0.19 mL/min/mL for FDG) were comparable with the liver blood flow (F = 1.02 +/- 0.05 mL/min/mL). As required physiologically, the extracellular volumes estimated using the dual-input function were larger than the hepatic blood volume. The linear Gjedde-Patlak analysis produced parameter estimates that were unaffected by the choice of input function, because this analysis was confined to time scales for which the arterial-input and dual-input functions were very similar. CONCLUSION: Compartmental analysis of MG and FDG kinetics using dynamic PET data requires measurements of dual-input activity concentrations. Using the dual-input function, physiologically reasonable parameter estimates of K1, k2, and Vp were obtained, whereas the use of conventional arterial sampling underestimated these parameters compared with independent measurements of hepatic flow and hepatic blood volume. In contrast, the linear Gjedde-Patlak analysis, being less informative but more robust, gave similar parameter estimates (K, V) with both input functions.

3-O-Methylglucose↗
PubMed2000

Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo.

BACKGROUND: Multidrug resistance (MDR) mediated by expression of MDR1 P-glycoprotein (Pgp) represents one of the best characterized barriers to chemotherapy in cancer patients. Positron emission tomography (PET) agents for analysis of Pgp-mediated drug transport activity in vivo would enable noninvasive assessment of chemotherapeutic regimens and MDR gene therapy. RESULTS: Candidate Schiff-base phenolic gallium(III) complexes were synthesized from their heptadentate precursors and gallium(III)acetylacetonate. Crystal structures demonstrated a hexacoordinated central gallium with overall trans-pseudo-octahedral geometry. Radiolabeled (67)Ga-complexes were obtained in high purity and screened in drug-sensitive (Pgp(-)) and MDR (Pgp(+)) tumor cells. Compared with control, lead compound 6. demonstrated antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Futhermore, compared with wild-type control, quantitative pharmacokinetic analysis showed markedly increased penetration and retention of 6. in brain and liver tissues of mdr1a/b((-/-)) gene disrupted mice, correctly mapping Pgp-mediated transport activity at the capillary blood-brain barrier and hepatocellular biliary cannalicular surface in vivo. CONCLUSIONS: These results indicate that gallium(III) complex 6. is recognized by MDR1 Pgp as an avid transport substrate, thereby providing a useful scaffold to generate (68)Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Incidence and characterization of integrons, genetic elements mediating multiple-drug resistance, in avian Escherichia coli.

Antibiotic resistance among avian bacterial isolates is common and is of great concern to the poultry industry. Approximately 36% (n = 100) of avian, pathogenic Escherichia coli isolates obtained from diseased poultry exhibited multiple-antibiotic resistance to tetracycline, oxytetracycline, streptomycin, sulfonamides, and gentamicin. Clinical avian E. coli isolates were further screened for the presence of markers for class 1 integrons, the integron recombinase intI1 and the quaternary ammonium resistance gene qacEDelta1, in order to determine the contribution of integrons to the observed multiple-antibiotic resistance phenotypes. Sixty-three percent of the clinical isolates were positive for the class 1 integron markers intI1 and qacEDelta1. PCR analysis with the conserved class 1 integron primers yielded amplicons of approximately 1 kb from E. coli isolates positive for intI1 and qacEDelta1. These PCR amplicons contained the spectinomycin-streptomycin resistance gene aadA1. Further characterization of the identified integrons revealed that many were part of the transposon Tn21, a genetic element that encodes both antibiotic resistance and heavy-metal resistance to mercuric compounds. Fifty percent of the clinical isolates positive for the integron marker gene intI1 as well as for the qacEDelta1 and aadA1 cassettes also contained the mercury reductase gene merA. The correlation between the presence of the merA gene with that of the integrase and antibiotic resistance genes suggests that these integrons are located in Tn21. The presence of these elements among avian E. coli isolates of diverse genetic makeup as well as in Salmonella suggests the mobility of Tn21 among pathogens in humans as well as poultry.

Animals↗
PubMed1997

Hepatic ICG removal in the pig depends on plasma protein and hematocrit: evidence of sinusoidal binding disequilibrium and unstirred water layer effects.

The influence of binding protein concentration and hematocrit on hepatic uptake of indocyanine green (ICG) was studied in anesthetized pigs during constant infusion of ICG. By exchange transfusions, we either substituted plasma protein with dextran 70 (n = 8) or changed hematocrit (n = 8). Intrinsic hepatic clearance of ICG, K, was calculated from plasma flow rate and concentrations in peripheral artery and liver vein after correction for extrahepatic distribution. By analyzing the relative change of K versus either the protein dilution factor or the change in plasma volume fraction (1-hct), we evaluated four current models for hepatic uptake of protein-bound substances even though a number of model parameters were unknown (parameter-free testing). Protein dilution factors (unitless) of 0.506 +/- 0.027, 0.673 +/- 0.011, and 0.749 +/- 0.028 were associated with inverse K ratios of 0.621 +/- 0.025, 0.758 +/- 0.021, and 0.817 +/- 0.013. These data rejected the traditional hypothesis that ICG uptake is proportional to the unbound concentration. They were compatible with development of binding disequilibrium along the sinusoidal lumen, an unstirred water layer close to the hepatocyte surface, or facilitated uptake from the bound pool. A plasma volume ratio [(1-hct2)/(1-hct1)] of 1.14 +/- 0.02 was associated with a K ratio of 1.07 +/- 0.02 (P = .01). Only sinusoidal binding disequilibrium predicted this finding, whereas an additional unstirred water layer effect could not be excluded. The observations could be simulated by a model that included both of these effects. Thus, neither the relative changes of K nor the absolute K values required the assumption of facilitated uptake from the bound pool. The parameter-free design presented may be useful with other ligands in intact animals.

Animals↗
PubMed1996

The kinetics of continuously infused indocyanine green in the pig.

Indocyanine green (ICG) is used in cardiology and hepatology for the estimation of cardiac output, liver function, and splanchnic blood flow. ICG is bound to plasma proteins and ultimately excreted by the liver. We studied the whole body kinetics of ICG during constant infusion in pigs weighing 30-40 kg. The conventional kinetic model (backflux model) assumes that deviations from one-compartmental linear kinetics is caused by backflux from a liver storage to plasma, and that no extravascular, extrahepatic distribution takes place. This model was tested against an alternative (redistribution) model postulating that temporary redistribution of ICG into an extrahepatic extravascular storage was responsible for the deviations while the hepatic uptake was a one-way first-order process. A mathematical analysis of the two models showed that they predicted different time courses of the hepatic extraction fraction of ICG. Thus, with blood sampling from both a peripheral artery and a hepatic vein, a discriminative model-testing experiment was possible. This test required a first-order steady-state hepatic removal of ICG which was confirmed in 7 experiments with infusion rates varied in a stepwise fashion (0.133 +/- 0.003, 0.269 +/- 0.010, 0.547 +/- 0.020 and 0.130 +/- 0.003 mumol.min-1). In the model-testing experiments (n = 10) ICG was infused at a constant rate of 0.135 +/- 0.07 mumol.min-1. The mean concentration in peripheral artery (microM) was well fitted by the biexponential function C(t) = 0.476.(1-0.632.e-0.216.1-0.368.e-0.0172.1). The time course of the observed hepatic extraction fraction was significantly different (p = 0.004) from that predicted from the backflux model but in agreement (p = 0.98) with the new model assuming hepatic removal to be a one-way process and implying temporary ICG redistribution into an extrahepatic, extravascular storage with an apparent volume of 0.144 +/- 0.023 L.Kg-1. Accordingly, extravascular ICG was demonstrated in a number of different tissues after 4-hr infusion (n = 3). If ICG is used to estimate hepatic blood flow according to Fick's principle, the use of a backflux model to correct for non-steady-state conditions will lead to an overestimation of hepatic blood flow of 28% after 25-min infusion, 16% after 50 min, and 6% after 100 min. The study indicated that distribution of ICG between plasma and tissues is not instantaneous, and that the time course of the redistribution itself significantly influences whole body kinetics. Comparison with a previously published study by Ott, Keiding, and Bass of ICG kinetics after bolus injection suggested that a two-compartment model was insufficient and that the kinetics for the exchange of ICG between plasma and the redistribution space may be nonlinear. The study demonstrates how blood sampling on both sides of the eliminating organ can expose the influence of redistribution. The discriminative model test for constant infusion experiments is novel and may be useful with other ligands.

Albumins↗
PubMed1996

Sex differences in initial clearance of palmitate by human hepatocytes.

To determine if the sex differences in clearance of long chain fatty acids by the liver observed in the rat are relevant to humans, the authors isolated hepatocytes from human adult males and females (five per group) and measured the initial (unidirectional) clearance of [3H]-palmitate from buffer containing albumin. The clearance was significantly higher (about twofold) in hepatocytes from females because of a higher permeability of the plasma membrane to the fatty acid. The livers had been perfused with University of Wisconsin (UW) solution and stored for 12-16 h before isolation of the cells. The magnitudes of the clearances in humans were similar to those in the rat when the livers were stored similarly, but lower than in cells isolated from fresh rat liver. When hepatocytes isolated from fresh rat liver were stored in UW solution, clearance of [3H]-palmitate was unaffected. Thus, hepatocytes prepared from intact liver stored for several hours in UW solution do not have as good preservation of function as hepatocytes isolated from fresh liver and then stored in UW solution.

Adolescent↗
PubMed1995

Testing a model of aging in animal experiments.

A stochastic model of aging is developed in terms of accumulation and expression of intracellular lesions caused by environment or intrinsic genetic program. In contrast to the commonly used Gompertz-Makeham approach to the parametric analysis of mortality data, the model yields a hazard function that is bounded from above. For testing the model in experiments aimed at studying animal longevity, a Kolmogorov-type statistical test is presented with regard to the hypothesis involving unknown parameters. Examples concerning longevity of intact animals of two different species, as well as the effect of a prolonged irradiation at a low dose rate, are given to illustrate the model application and goodness-of-fit testing. The results of the analysis of published data show that the rate of lesion formation is not sustained at a constant level throughout life, though in some cases its variations with age can be considered negligible.

Aging↗
PubMed1994

Microvascular anastomoses utilizing new intravascular stents.

Evolving microsurgical technique has allowed for the anastomosis of smaller diameter vessels. Standard suture anastomoses cause a measure of stenosis and intimal damage during application and therefore cannot be dependably used in the anastomosis of very small vessels. We developed and tested a fibrin glue-based anastomosis applied over a meltable stent made of mono- di- and tri-glycerides. In vivo rodent studies using the 0.35 mm diameter inferior epigastric artery have shown immediate and short-term patency rates better than those associated with suture technique. The stent technique is significantly faster and easier than the suture technique. The glyceride stent method suffers from decreased late patency due to aneurysm formation. In addition, we developed a glyceride-coated polyethylene glycol-based stent for use in lasered anastomoses. Work on both projects is ongoing.

Anastomosis, Surgical↗
PubMed1994

Hepatic removal of two fractions of indocyanine green after bolus injection in anesthetized pigs.

In the anesthetized pig, we studied the kinetics after intravenous bolus injection of two fractions of indocyanine green (ICG): the genuine ICGg (95-99% of total) and a degradation product, ICGdp (1-5%). Plasma concentrations were followed in the carotid artery and a hepatic vein. ICGg disappearance curves (n = 7) were biexponential with rate constants alpha = 0.189 +/- 0.021 min-1 and beta = 0.0356 +/- 0.0061 min-1. The hepatic extraction fraction was constant with time. A detailed mathematical analysis showed this to be in disagreement with the conventional assumption that the biexponential plasma disappearance curve is a result of backflux from the liver storage to plasma. In contrast, our observations were predicted by an alternative model assuming temporary extrahepatic, extravasal redistribution during first-order, one-way hepatic uptake. Nevertheless, when a large bolus of sulfobromophthalein (BSP) was injected 20 min after ICG, a net backflux of ICG could be demonstrated, presumably due to countertransport. Thus a sufficient description of ICGg kinetics must include the complex kinetic behavior of the hepatic membrane carrier involved. Mass spectrometry suggested that ICGdp is formed by two ICGg molecules. Plasma elimination of ICGdp was slower (alpha = 0.0094 +/- 0.0007 min-1). Analysis of the bile after bolus injection (n = 2) of ICGdp revealed two possible metabolites of ICGdp that were not found in urine. Since BSP injection did not alter the ICGdp disappearance curve, ICGdp is probably not taken up by the same hepatic membrane carrier as ICGg.

Animals↗
PubMed1994

Effects of gender and pregnancy on hepatocellular uptake of palmitic acid: facilitation by albumin.

The human serum albumin (HSA)-dependent unbound clearance (Clu) of [3H]palmitic acid (PA) by hepatocyte suspensions isolated from immature and mature male and female and pregnant female rats was studied. The Clu values obtained experimentally were compared with the predictions of a noncompartmental diffusion-reaction (Bass-Pond) theory for the cellular uptake of protein-bound ligands. In all groups, as the concentration of HSA (Ca) was increased, there was a striking increase in Clu. These enhancement factors were predicted by the theory. Adult females had higher Clu values at high Ca values than males or immature females. Furthermore, at high Ca values, Clu in pregnant animals was twice as high as in the nonpregnant animals and four times as high as in the aged-matched males. The absolute values of Clu obtained experimentally in both pregnant and nonpregnant females exceeded the maximal predictions of the theory, using reasonable values of all of the parameters. Thus, according to current data on the physicochemical characteristics of the uptake system, the study demonstrates that some specialized process exists to facilitate hepatocellular uptake of fatty acid from albumin, and that it is potentiated by the female sex hormones.

Aging↗
PubMed1993

A stochastic model of hormesis.

In order to describe the life-prolonging effect of some agents that are harmful at higher doses, ionizing radiations in particular, a stochastic model is developed in terms of accumulation and progression of intracellular lesions caused by the environment and by the agent itself. The processes of lesion repair, operating at the molecular and cellular level, are assumed to be responsible for this hormesis effect within the framework of the proposed model. Properties of lifetime distributions, derived for analysis of animal experiments with prolonged and acute irradiation, are given special attention. The model provides efficient means of interpreting experimental findings, as evidenced by its application to analysis of some published data on the hormetic effects of prolonged irradiation and of procaine on animal longevity.

Animals↗
PubMed1993

Enhancement of unbound clearance of ICG by plasma proteins, demonstrated in human subjects and interpreted without assumption of facilitating structures.

The kinetics of hepatic removal of protein-bound substances were studied in nine human subjects with various liver diseases by the use of indocyanine green as a model substance. Intrinsic hepatic clearance of indocyanine green was measured by means of a constant infusion of indocyanine green and concentration measurements of indocyanine green in arterial and hepatic venous plasma samples. During the indocyanine green infusion, 1-1.51 of dextran-70 was given whereby a stable dilution of the plasma protein concentration by a factor of 0.6-0.8 was obtained. In each of the subjects, the intrinsic clearance of indocyanine green increased after the protein dilution (range 11-64%). Elimination of ethanol (not protein bound), similarly assessed, was not significantly changed. The traditional hypothesis that unbound clearance (intrinsic clearance divided by the free fraction of the ligand) is independent of protein concentration was refuted since in each of the subjects the protein dilution was followed by a reduction of the unbound clearance of ICG (P < 0.005, n = 9). We examined whether these observations imply some special mechanism (e.g. a hepatocyte protein receptor) by which the unbound clearance is enhanced by the binding protein(s). The previously developed pseudofacilitation model--describing the effects of ligand-protein diffusion and dissociation in an unstirred plasma layer near the hepatocyte--was extended to the case of a mixture of binding proteins, and parameter-free bounds were derived to predict the response of intrinsic clearance to protein dilution. The observed changes of the intrinsic clearance values did not violate these bounds (P < 0.002, n = 9). Thus no facilitating mechanisms are necessary to account for the observed deviations from the traditional hypothesis.

Adult↗
PubMed1993

Plasma elimination of indocyanine green in the intact pig after bolus injection and during constant infusion: comparison of spectrophotometry and high-pressure liquid chromatography for concentration analysis.

Indocyanine green is used to estimate liver blood flow rate and hepatic intrinsic clearance. However, its use as a test substance for studies of liver function has been limited by two puzzling kinetic observations: a biexponential plasma decay after bolus injection with an extremely slow late phase and an apparently steadily decreasing clearance value during constant infusion. These observations have been made with spectrophotometric concentration analysis. In anesthetized 30- to 40-kg pigs, we examined plasma concentration curves of indocyanine green after intravenous bolus injection and during long-term infusion. We compared spectrophotometry with high-pressure liquid chromatography for measurement of plasma indocyanine green concentration. In freshly prepared commercially available indocyanine green, high-pressure liquid chromatography could separately measure two fractions, the genuine indocyanine green (97% to 99% of total) and an in vitro degradation product (1% to 3%). Because their spectra were nearly identical, these fractions could not be distinguished by spectrophotometry. After intravenous administration both fractions were identified in the plasma by high-pressure liquid chromatography. In the first series (n = 6) 25 mg of indocyanine green was injected intravenously for 5 min. When analyzed by high-pressure liquid chromatography, the genuine indocyanine green plasma concentration decay was biexponential with rate constants 0.196 +/- 0.021 (mean +/- S.E.M., n = 6) and 0.0372 +/- 0.0064 min-1. The degradation product of indocyanine green decayed almost monoexponentially, with a rate constant of 0.0093 +/- 0.0002 min-1. With spectrophotometry a biexponential decay was observed with rate constants 0.130 +/- 0.012 and 0.0095 +/- 0.0001 min-1. The biexponential decay of indocyanine green after spectrophotometry was the result of codetermination of the two fractions: genuine indocyanine green was responsible for initial phase, and the degradation product of indocyanine green was responsible for the late phase. In the second series (n = 9), indocyanine green was administered as a constant intravenous infusion. From 90 to 240 min the intrinsic hepatic clearance of genuine indocyanine green did not change detectably with time. In contrast, the degradation product of indocyanine green never reached steady-state concentrations. Because of code-termination of these two indocyanine green fractions, the apparent intrinsic hepatic clearance of indocyanine green estimated from spectrophotometry was steadily decreasing by 8.9% +/- 1% per hour of its initial value. At the same time estimation of liver plasma flow rate based on Fick's principle was not affected by the choice of analytical methodology. These observations indicate that high-pressure liquid chromatography is superior to spectrophotometry for kinetic analysis of indocyanine green elimination.

Animals↗
PubMed1992

Intrinsic hepatic clearance of indocyanine green in the pig: dependence on plasma protein concentration.

Intrinsic hepatic clearance (K) of indocyanine green (ICG) is used as a quantitative measure of liver function. ICG is tightly bound to plasma proteins. The purpose of this study was to examine the effect of changes of plasma protein concentration on K in anaesthetized pigs with intact hepatic circulation. In addition, an attempt was made to evaluate the corresponding changes of the unbound intrinsic clearance of ICG. The plasma protein concentration was changed by exchange of plasma with either dextran-70 or donor pig plasma. Plasma albumin concentration was measured in a peripheral artery and changes of the concentrations of other plasma proteins were assumed to parallel those of albumin. ICG was given as a constant infusion and K was calculated from peripheral artery and hepatic vein concentrations of ICG according to the sinusoidal perfusion model. One experimental series comprised 3 measurement periods: From Period 1 to Period 2 (eight animals) albumin concentration was decreased by 36.6 +/- 6.5% (Mean +/- SD). This was associated with an increase of K of 32.8 +/- 28.8% (P = 0.004). From Period 2 to 3 (five animals) albumin was increased by 13.2 +/- 3.2% and K decreased by 18.5 +/- 8.3% (P = 0.03). In the second experimental series (eight animals), albumin concentration was increased by 21.6 +/- 10.3% and K decreased by 20.3 +/- 8.1% (P = 0.001). For both series, changes in albumin concentration were associated with oppositely directed changes of K in 20 out of 21 comparisons (P less than 0.001). Thus K depends not only on hepatocyte function but also on plasma protein concentration. This finding should affect interpretation of K when used as a liver function test. Changes of the unbound intrinsic clearance of ICG were examined indirectly by means of the K.a product (a: albumin concentration). According to the overall evaluation of the data the unbound intrinsic clearance of ICG was not affected by the changes in plasma protein concentration, but the results were internally inconsistent, apparently due to a time-dependency of the K.a product. We suggest this to be due to a slow but steady decrease of the 'background' K. After correction for the average decrease of K of 0.102% per min our data were in accordance with the hypothesis that the unbound clearance of K was enhanced by the binding protein(s) of ICG.

Animals↗
PubMed1992

Uptake of palmitate by hepatocyte suspensions: facilitation by albumin?

Albumin-dependent uptake of unbound [3H]palmitic acid by hepatocytes isolated from female rat livers was studied and the experimental results compared with the predictions of a noncompartmental diffusion-reaction theory for the cellular uptake of protein-bound ligands. The outright theoretical predictions involve values for the parameters of the system, some newly measured (hepatocyte radii and the rate constant for the dissociation of palmitate-albumin complex) and some taken from the literature (diffusion coefficients and the equilibrium association constant for the palmitate-albumin complex). The measured unbound clearance of [3H]palmitic acid, defined as the initial uptake velocity divided by the unbound [3H]palmitic acid concentration in the medium, was enhanced 6.6-fold as the concentration of human serum albumin was increased from approximately 5 to 480 microM. This enhancement factor was predicted by the theory, according to which the enhancement reflects codiffusion of bound ligand across the unstirred layer adjacent to the cell membrane and, therefore, an increased delivery of unbound ligand to the cell surface. In contrast, the absolute magnitude of the unbound clearance was consistent with the theory only for the lowest published value for the equilibrium association constant, 15 microM-1. For higher published values (62 and 94 microM-1), the magnitude of the unbound clearance observed experimentally was severalfold higher than that predicted by the theory. If in fact the association constant exceeds 30 microM-1, the data would imply that an albumin-dependent facilitation mechanism exists which enhances the availability of palmitate to the cell over and above the enhancement predicted by the diffusion-reaction theory.

Animals↗
PubMed1991

Hepatic uptake of protein-bound ligands: extended sinusoidal perfusion model.

Traditional transport models have failed to account for uptake of many protein-bound ligands by liver and other tissues when the concentration of plasma albumin or other binding protein is varied. In this paper, we extend the standard sinusoidal perfusion model to include the effects of slow dissociation of the ligand from albumin and of diffusion across extracellular barriers such as the unstirred layer. We then use experimental data for uptake of oleate from albumin solutions (1:10 molar ratio) by perfused female rat livers to test this model. Unlike the standard model, the extended model closely conformed to observed uptake rates over a wide concentration range (0.015-0.45 mM albumin). The extension, which is conceptually simple, is based on widely accepted physiological principles. It requires only the introduction of two dimensionless ratios into the standard model: the ratio of the mean unbound ligand concentration actually present within the capillary or sinusoid to its equilibrium value, and the ratio of the permeability of the membrane plus associated extracellular diffusion barriers to the permeability of the membrane alone. The resulting model simplifies to the standard sinusoidal perfusion model when both ratios approximate unity. We first develop the model for steady influx alone because our data suggest that little efflux of oleate occurred over the time course of the current study. In an appendix, we extend the model to include the effects of efflux and metabolism. The new model offers an alternative for explaining uptake kinetics of protein-bound ligands that cannot be explained by less complete traditional models.

Animals↗